Why isn’t tranexamic acid used more often in routine practice?

The other day at an interdisciplinary rounds meeting at the hospital, one of our nurses who is also an emergency medical technician mentioned that in Britain injured patients receive tranexamic acid before arriving at the hospital because it reduces death from bleeding.

“What’s that?” I said.

I kind of barely remembered hearing this medication’s name associated with the treatment of a rare disease, but not treatment of trauma. So I was guessing that this was some drug that was invented long ago which had been found to be quite effective in other countries, but has not been really optimally used in the US because it is generic and therefore unlikely to make drug companies money.

Bingo.

Here’s the story, as far as I can determine.

Tranexamic acid is a relatively simple cyclic molecule that blocks the fibrinolytic process, that is the natural breakdown of blood clots in the body. In the setting of any injury, especially severe ones, fibrinolysis is intensified, leading to a condition of excess bleeding in trauma victims. This is hardly ideal, and tranexamic acid can help reverse this.

It also appears to have an effect on reducing inflammation, which may be even more significant. There have been a couple of major studies in the last 3 years showing significantly better outcomes in patients who have traumatic injury and who are treated with tranexamic acid intravenously soon after injury. The most recent study, published in the Archives of Surgery, looked at 896 patients injured in the military from registries in the UK and the US and identified the subset treated with tranexamic acid. Although this group was generally more severely injured, the mortality rate was significantly lower, 6.5% lower, than the group that had not received the drug.

In very seriously injured patients, those who received massive transfusion of blood products, the difference in survival was nearly 14%. It is not often that we see an effect this powerful, especially in a group like this who are healthy and will likely have long and productive lives after being saved. An earlier study, published in 2011 in the Lancet entitled CRASH-2 showed similar results in civilian trauma victims, with a double blind prospective design.

The Cochrane Collaboration, a group of researchers who review randomized controlled trials concluded that tranexamic acid was safe and effective in reducing mortality in trauma patients without increasing adverse events.

So maybe it’s actually very expensive, then. I called our hospital pharmacy to ask about that. Apparently a gram of it costs about $44. The usual protocol for trauma is 1 gram intravenously right away and then another gram over the next 8 hours. So $88 times 100 equals $8800 to save 6.5 lives (using the data from the military study), $1353 per life saved. That’s pretty cheap. And since it probably reduces the severity of illness in the rest of the patients treated, it may end up reducing overall treatment costs.

Presently the only FDA (Food and Drug Administration) approved indication for this drug in the US is an oral formulation to be used for women with heavy periods and intravenously for prevention of dental bleeding in hemophiliacs. It is also used, off-label, to reduce transfusion requirements in total joint surgeries (that’s why we have it in our pharmacy), also in some places for prostate surgery, general surgery, gastrointestinal hemorrhage, bleeding around pregnancy and delivery and bleeding within the eye. It reduces the frequency of attacks of swelling in a condition called hereditary angioedema, which is rare, and was why I had even heard of it in the past.

It has been available over the counter for years in Europe, marketed for heavy menstrual bleeding. The injectable formulation is also on the World Health Organization’s list of 350 essential medicines which are considered safe and effective and necessary worldwide.

So what are its side effects? It may increase the risk of blood clots in the legs and lungs, but studies have shown this to be far less of an issue than one might guess, and it looks like the lives saved far outweigh this risk. The CRASH-2 study showed that there might be a slight risk of increasing mortality if it was given to trauma patients more than 3 hours after their injury.

Why is it not FDA approved for reduction of bleeding in trauma and other similar situations for which there is ample evidence of safety and efficacy? The FDA approves drugs and devices when approval is requested, and usually the drug or device manufacturers who stand to make money from an FDA approved indication are the ones to make the request. I suspect there has been no request for approval for these other indications. Just because it is not FDA approved to reduce bleeding in trauma and surgery doesn’t mean it can’t be used, but physicians have a certain hesitance to use unfamiliar drugs “off-label.”

So the story of tranexamic acid is another excellent example of how simpler, cheaper and sometimes more effective treatments are not being widely used in the US, even though our patients may receive exorbitantly expensive medications and treatments of dubious or minimal benefit. This is because we allow powerful pharmaceutical companies to inform our practice. Sometimes this actually works, when companies produce groundbreaking innovations and encourage us to adopt them.

It is unlikely, though, to help us find creative uses for inexpensive drugs that have been around a long time. This dynamic may mean that 6 or so people of the 100 who are probably just now being involved in accidents with bleeding will die when they would not have if use of this drug part of our routine practice.

Why isn’t tranexamic acid used more often in routine practice? 1 comments

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http://www.drsocial.org brettmd

Physicians who are uncomfortable using any drugs off label are probably not practicing good medicine or refer to physicians who do. You present an excellent case where a physician can use their knowledge of medication, and understanding of the pharmacopathophysiology of disease to use an approved medication for another condition. This is not the same as using a medication with no approval for a therapy. Such cases are probably best usually classified as “research,” and examined in clinical trials with the surrounding regulatory process.

You provide an excellent example of what may be appropriate implementation of off-label use. A parallel to this is medications for ADHD. Adderall’s volume of distribution varies inversely with body weight. Using the doses that are effective in children in heavier adults is probably why ADHD medications are considered less effective in adults. http://www.ncbi.nlm.nih.gov/pubmed/14599383